Irritable bowel syndrome (IBS) is the most common of all gastrointestinal disorders, affecting 10-20% of the general population and accounting for more than 50% of all patients with digestive complaints. However, studies suggest that only about 10% to 50% of those afflicted with IBS actually seek medical attention. Patients with IBS present with disparate symptoms such as, for example, abdominal pain predominantly related to defecation, diarrhea, constipation or alternating diarrhea and constipation, abdominal distention, gas, and excessive mucus in the stool. More than 40% of IBS patients have symptoms so severe that they have to take time off from work, curtail their social life, avoid sexual intercourse, cancel appointments, stop traveling, take medication, and even stay confined to their house for fear of embarrassment. The estimated health care cost of IBS in the United States is $8 billion per year (Talley et al., Gastroenterol., 109:1736-1741 (1995)).
IBS patients are classified into three groups according to their predominant bowel symptoms: constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D) and IBS with alternating symptoms of diarrhea and constipation (IBS-M), and unsubtyped IBS (IBS-U). In current clinical practice, diagnosis of IBS is based on the Rome III criteria and according to the symptoms presented by the patients plus the exclusion of other GI disorders. There are no specific biological, radiographic, endoscopic or physiological biomarkers that can be used to identify this disorder.
Irritable bowel syndrome is a heterogeneous gastrointestinal (GI) function disorder. There is increasing evidence pointing to the involvement of the immune system in its pathogenesis. GI infection may be a triggering factor for causing the onset of IBS symptoms. On the other hand, IBS is often described as a “brain-gut disorder”. Alterations in GI motility and secretion mediated by dysregulation of the 5-HT signaling pathway may underlie the irregularities in bowel habits. Activation of mast cells in proximity to colonic nerves correlated with the abnormal pain experienced by patients with IBS. Mast cells are well known to be capable of producing and releasing a variety of inflammatory mediators upon activation. However, it is not clear how these different pathways communicate with each other and whether their interactions behave in the same manner in IBS patients as it is in healthy subjects.
The precise pathophysiology of IBS remains to be elucidated. While gut dysmotility and altered visceral perception are considered important contributors to symptom pathogenesis (Quigley, Scand. J. Gastroenterol., 38(Suppl. 237):1-8 (2003); Mayer et al., Gastroenterol., 122:2032-2048 (2002)), this condition is viewed as a stress-related disorder characterized by disturbed brain-gut communication, enteric infection, intestinal inflammation, and/or altered microbiota (see, FIG. 1). Recently, roles for enteric infection and intestinal inflammation have also been proposed. Studies have documented the onset of IBS following bacteriologically confirmed gastroenteritis, while others have provided evidence of low-grade mucosal inflammation (Spiller et al., Gut, 47:804-811 (2000); Dunlop et al., Gastroenterol., 125:1651-1659 (2003); Cumberland et al., Epidemiol. Infect., 130:453-460 (2003)) and immune activation (Gwee et al., Gut, 52:523-526 (2003); Pimentel et al., Am. J. Gastroenterol., 95:3503-3506 (2000)) in IBS. The enteric flora (e.g., gut microbiome) has also been implicated, and a recent study demonstrated the efficacy of the probiotic organism Bifidobacterium in treating the disorder through modulation of immune activity (Simren et al., Gut, 62:159-176 (2013)).
There is a growing body of evidence supporting the role of antimicrobial antibodies, stress hormones, inflammatory cytokines, and mast cell markers in various intestinal diseases or disorders. For instance, the antimicrobial antibodies OmpC, Cbir1, FlaX and Fla2 have been proven to be valuable biomarkers of inflammatory bowel disease (IBD). Subsets of antibodies to Escherichia coli K12 proteins (e.g., Era, FocA, FrvX, GabT, YbaN, YcdG, YhgN, and YidX) can be used to distinguish between individuals with Crohn's Disease (CD) and healthy controls, and between individuals with CD and ulcerative colitis (Chen et al., Mol. Cell Proteomics, 8:1765-1776, (2009)). Individuals with post-infectious small intestine bacterial outgrowth (SIBO) associated with IBS which is often caused by infection from Campylobacter jejuni (C. jejuni, Cj), Escherichia coli (E. coli, Ec), Salmonella enteritidis (S. enteritidis, Se), Shigella flexneri (S. flexneri, Sf), may possess antibodies against flagellin proteins of the infecting bacteria (Spiller R and Garsed K., Gastroenterology, 136:1979-1988 (2009)).
Increased mast cell infiltration and activation in distal gut segments are associated with symptom onset and severity of IBS. These cells are also implicated in the elevated response of visceral afferent nerves to mucosal stimulus in IBS patients. Mast cell hyperplasia is commonly observed following infection by these bacteria in both post-infectious IBS and non-post-infectious IBS. Measurements of mast cell markers such as β-tryptase, histamine and prostaglandin E2 (PGE2) have important implications in the clinical diagnosis of IBS. Detailed methods of using mast cell markers to aid in the diagnosis of IBS are described in U.S. Pat. Nos. 8,114,616 and 8,709,733, the disclosures of which are hereby incorporated by reference in their entireties for all purposes.
IBS patients typically experience abnormal gut motility and visceral hypersensitivity mediated by the brain-gut axis and the gut microbiome (FIG. 1). In stress-sensitive disorders including IBS, stress hormones of the hypothalamic-pituitary-adrenal axis (HPA) axis, such as gut hormones, serotonin, adrenocorticotropin hormone (ACTH), cortisol, corticotropin-releasing hormone, and catecholamine are released, thus controlling the physiological function of, for example, the gut. Dysregulation of the brain-gut axis including the metabolite driven pathways, such as the tryptophan pathway, kynurenine pathway and serotonin pathway (FIG. 2) can adversely affect gastrointestinal function by decreasing motility and increasing pain or discomfort. Therapeutics drugs directed to the serotonin pathway are currently under investigation for the treatment of IBS. Dysregulation of intestinal bile acid secretion and absorption is also associated with IBS (FIG. 3). Some studies have also shown that gastrointestinal function is affected by the gut microbiome (FIG. 4). For instance, diet, antibiotics, pathogens, and the host's immune response can change the gut's microbiome community, which in turn, can alter intestinal function.
In view of the foregoing, there is a need in the art for methods for diagnosing IBS in an individual by monitoring the brain-gut-microbiome axis. The present invention satisfies this and other needs.